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Many patients with non-small cell lung cancer do not receive guideline-recommended, biomarker-directed therapy, despite the potential for improved clinical outcomes. Access to timely, accurate, and comprehensive molecular profiling, including targetable protein overexpression, is essential to allow fully informed treatment decisions to be taken. In turn, this requires optimal tissue management to protect and maximize the use of this precious finite resource. Here, a group of leading thoracic pathologists recommend factors to consider for optimal tissue management. Starting from when lung cancer is first suspected, keeping predictive biomarker testing in the front of the mind should drive the development of practices and procedures that conserve tissue appropriately to support molecular characterization and treatment selection., (© 2023 The Authors. Histopathology published by John Wiley & Sons Ltd.)

PD-L1 test is recommended in different types of tumors to select patients eligible for immune checkpoint inhibitors (ICI) therapy. Several factors make this test challenging in metastatic triple-negative breast cancer (mTNBC). Different assays and platforms are available, each associated with distinct scoring systems and threshold values specific to the ICI compound used, i.e. CPS≥10 for pembrolizumab and IC ≥ 1 % for atezolizumab. Our objective was to assess the consistency of PD-L1 testing in mTNBC by examining interobserver and interassay reproducibility. We assessed n = 60 mTNBC samples for PD-L1 testing using 22C3 pharmDx assay on a Dako Autostainer Link 48 and VENTANA PD-L1 (SP263) on a Ventana BenchMark Ultra. Additionally, a subset of n = 19 samples was tested using the SP142 assay, also on the Ventana BenchMark Ultra. CPS with both 22C3 and SP263 was independently evaluated by five pathologists, all certified PD-L1 trainers. The IC with SP142 was assessed by three of these pathologists, who have particular expertise in breast pathology. Following the computation of the intraclass correlation coefficient (ICC) for each assay and their respective thresholds, we assessed the agreement between different raters and assays using Fleiss's κ, with a 95 % confidence interval (CI). Overall, we observed a significant (p < 0.001) ICC with both CPS assays [22C3 = 0.939 (CI:0.913-0.96); SP263 = 0.972 (CI:0.96-0.982); combined 22C3-SP263 = 0.909 (CI:0.874-0.938)]. Fleiss's κ confirmed an almost perfect agreement among pathologists and assays: 22C3 = 0.938 (CI:0.857-1.018); SP263 = 0.972 (CI:0.890-1.052); combined 22C3-SP263 = 0.907 (CI:0.869-0.945). Perfect inter-rater agreement was reached considering IC. This study establishes the reliability of assessing CPS in mTNBC using either the 22C3 pharmDx, as employed in the KEYNOTE studies, or the VENTANA SP263 assay. Each assay must be used on its designated platform, namely the Dako for 22C3 pharmDx and the Ventana for VENTANA SP263. It is important to remark that CPS and IC identify different patient cohorts and, therefore, are not interchangeable., Competing Interests: Declaration of competing interest M.I. has received honoraria from Agilent Technologies Denmark ApS. B.C. has received honoraria from Merck Sharp and Dome (MSD), Novartis and Roche. C.C. served as advisory/consultancy role/speaker bureau for Roche, Pfizer, Eli Lilly, Novartis, AstraZeneca, Daiichi Sankyo, Gilead, Seagen and MSD, all outside the submitted work. G.C. reports funding from Astra Zeneca, Daichii Sankyo, Merck; consulting fees from BMS, Roche, Pfizer, Novartis, Lilly, Astra Zeneca, Daichii Sankyo, Merck, Seagen, Ellipsis; honoraria from Pfizer, Lilly; support for attending meetings from Roche, Pfizer. E.G-R has relevant relationship (advisory fees, honoraria, travel accommodation and expenses, grants and non-financial support) with AstraZeneca, Exact Sciences, GlaxoSmithKline (GSK), Novartis, Roche, Thermo Fisher Scientific unrelated to the current work. P.G. has received honoraria for consulting, advisory role, speaker bureau, travel, and/or research grants from Merck Sharp & Dohme (MSD), Novartis, AstraZeneca, Roche, BMS, Amgen, Pfizer and Eli Lilly. GdA has received honoraria from Merck Sharp and Dome (MSD), Novartis, AstraZeneca, Roche, and Daiichi Sankyo. N.F. has received honoraria for consulting, advisory role, speaker bureau, travel, and/or research grants from Merck Sharp & Dohme (MSD), Novartis, AstraZeneca, Roche, Menarini, Daiichi Sankyo, GlaxoSmithKline (GSK), Gilead, Diaceutics, Adicet Bio, Sermonix, Reply, Leica Biosystems. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We present a case of a woman with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma who received gefitinib for 2 years and obtained a partial response. The patient then developed liver metastasis and a breast lesion, displaying high estrogen receptor (ER) expression and harboring the same EGFR mutation. From the radiological studies, it was not possible to make a differential diagnosis between primary breast cancer and breast metastasis from lung cancer. After the removal of the breast nodule, thanks to the clinical history, radiology, and above all, molecular and immunohistochemical investigations, a diagnosis of breast metastasis from lung adenocarcinoma was made. This case emphasizes the importance of a comprehensive clinical, pathological, and molecular analysis in the differential diagnosis between primary breast cancer and metastases from extramammary tumor to guide adequate treatment decision making.

Introduction : The treatment scenario of lung cancer is rapidly evolving through time. In parallel, growing evidence is accumulating on different mechanisms of treatment resistance. Inter- and intra-tumor heterogeneity define the spatial and temporal tumor clonal evolution, that is at the basis of tumor progression and resistance to anticancer treatments. Areas covered : This review summarizes the available evidence on molecular heterogeneity in lung cancer, from diagnosis to the occurrence of treatment resistance. The application of novel molecular diagnostic methods to detect molecular heterogeneity, and the implications of understanding heterogeneity for drug development strategies are discussed, with focus on clinical relevance and impact on patients' survival. Expert opinion : The current knowledge of molecular heterogeneity allows to identify different molecular subgroups of patients within the same conventional tumor type. Deeper understanding of heterogeneity determinants and the possibility to comprehensively investigate tumor molecular patterns will lead to the development of personalized treatment approaches, with the final goal to overcome resistance and prolong survival in lung cancer patients.

The advances in understanding the inherited biological mechanisms of non-small cell lung cancer harbouring epidermal growth factor receptor (EGFR) mutations led to a significant improvement in the outcomes of patients treated with EGFR tyrosine kinase inhibitors. Despite these clinically impressive results, clinical results are not always uniform, suggesting the need for deepening the molecular heterogeneity of this molecularly defined subgroup of patients beyond the clinical and biological surface.The availability of tissue and blood-based tumour genotyping allows us to improve the understanding of molecular and genetic intratumor heterogeneity, driving the measurement of clonal evaluation in patients with lung cancer carrying EGFR mutations. Genetic diversification, clonal expansion and selection are highly variable patterns of genetic diversity, resulting in different biological entities, also a prerequisite for Darwinian selection and therapeutic failure.Such emerging pieces of evidence on the genetic diversity, including adaptive and immunomodulated aspects, provide further evidence for the role of the tumour microenvironment (TME) in drug-resistance and immune-mediated mechanisms. Matching in daily clinical practice, the detailed genomic profile of lung cancer disease and tracking the clonal evolution could be the way to individualise the further target treatments in EGFR-positive disease. Characterising the tumour and immune microenvironment during the time of the cancer evaluation could be the way forward for the qualitative leap needed from bench to bedside. Such a daring approach, aiming at personalising treatment selection in order to exploit the TME properties and weaken tumour adaptivity, should be integrated into clinical trial design to optimise patient outcome., Competing Interests: Competing interests: AP has received honoraria for consulting, advisory role or lectures from AstraZeneca, Agilent/Dako, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Merck Sharp & Dohme, Pfizer and Roche Genentech. UM has received personal fees from Boehringer Ingelheim, Roche, MSD, Amgen, Merck and AstraZeneca. FDM has served in a consultant/advisory role for AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Novartis, Roche Genentech, Takeda and Pfizer. CR has received speakers’ bureau from AstraZeneca and MSD, a research grant from the Lung Cancer Research Foundation–Pfizer, and research support from Guardant Health and Biomark; has an advisory board role with ARCHER, Inivata and Merck Serono; and hasconsulted for Mylan and Oncopass., (© Author (s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Purpose: Immunotherapy is a new standard first-line treatment for non-small cell lung cancers (NSCLC) with high programmed cell death-ligand 1 (PD-L1) expression (≥ 50%) and second-line treatment regardless of PD-L1 status, though not all patients benefit from this approach. Much effort is ongoing to identify robust prognostic and predictive biomarkers of response to immune checkpoint inhibitors, overcoming PD-L1 that appears limited in its ability to discriminate patient candidates to this new class of anticancer agents. The purpose of this research study is to identify potential new biomarkers for immunotherapy in lung cancer., Methods: Fifty-three consecutive patients with advanced NSCLC treated with nivolumab were enrolled in the study. All the patients received a blood analysis looking for the relationship between different populations of baseline white blood cells and granulocytic myeloid-derived suppressor cells (Gr-MDSC) detected by flow cytometry, to identify and characterize patients with poor likelihood of benefit from nivolumab in NSCLC second-line setting, regardless of clinical feature and PDL1 expression., Results: Univariate analysis showed that high baseline levels of Gr-MDSC and low baseline CD8/Gr-MDSC ratio are associated with significantly better (P = 0.02) response to immunotherapy treatment. Log-rank tests suggested a significant improvement in OS and PFS with high baseline levels of Gr-MDSC levels (≥ 6 cell/μl), low absolute neutrophil count (< 5840/μl), high eosinophil count (> 90 /μl), and NLR < 3. The multivariate analysis showed a statistically significant improvement for PFS (P = 0.003) and OS (P = 0.05) in favour of the identified good prognostic Gr-MDSC-linked asset group, compared with the poor prognosis group., Conclusion: The role of Gr-MDSC appears interesting as a potential biomarker in NSCLC patients receiving immune-checkpoint inhibitors. Further analyses are needed to confirmed and study in deep the role of these particular cells and their role in cancer response and progression during ICI therapy.

Background/aim: The role of anti-PD1/PD-L1 therapy (IO) in NSCLC harboring driver mutations is questionable. This study aimed to examine the efficacy of IO in patients with non-small cell lung cancer (NSCLC) with a KRAS mutation (KRAS + )., Patients and Methods: We retrospectively identified NSCLC patients harboring KRAS mutation treated with IO in our Institution. We analyzed the results in comparison to non-KRAS patients., Results: Among 328 consecutive KRAS + NSCLC patients, 43 (13.1%) received IO in our Institution. In parallel 117 non-KRAS NSCLC patients treated with IO were selected for comparison. The baseline characteristics were similar between the two groups. No significant difference was observed between KRAS + and non-KRAS patients in terms of mPFS (4.6 vs. 3.3 months, p=0.58) or OS (8.1 vs. 13.0 months, p=0.38)., Conclusion: KRAS mutations seem to be irrelevant for selecting patients for IO that could be therefore considered an effective therapy for NSCLC patients, independently of KRAS status., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Molecular profiling of advanced non-small cell lung cancers (NSCLC) is essential to identify patients who may benefit from targeted treatments. In the last years, the number of potentially actionable molecular alterations has rapidly increased. Next-generation sequencing allows for the analysis of multiple genes simultaneously., Aims: To evaluate the feasibility and the throughput of next-generation sequencing in clinical molecular diagnostics of advanced NSCLC., Methods: A single-institution cohort of 535 non-squamous NSCLC was profiled using a next-generation sequencing panel targeting 22 actionable and cancer-related genes., Results: 441 non-squamous NSCLC (82.4%) harboured at least one gene alteration, including 340 cases (63.6%) with clinically relevant molecular aberrations. Mutations have been detected in all but one gene ( FGFR1 ) of the panel. Recurrent alterations were observed in KRAS , TP53 , EGFR , STK11 and MET genes, whereas the remaining genes were mutated in <5% of the cases. Concurrent mutations were detected in 183 tumours (34.2%), mostly impairing KRAS or EGFR in association with TP53 alterations., Conclusions: The study highlights the feasibility of targeted next-generation sequencing in clinical setting. The majority of NSCLC harboured mutations in clinically relevant genes, thus identifying patients who might benefit from different targeted therapies., Competing Interests: Competing interests: EG-R and MB received consulting fees from ThermoFisher., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Context: - Molecular testing is essential for the diagnostic workup of patients with advanced non-small cell lung cancers. Cytology specimens from minimally invasive procedures, such as endobronchial ultrasound-guided transbronchial needle aspiration, are often the only available samples for these patients. The implementation of molecular diagnostic testing, and in particular next-generation sequencing-based testing, on these cytologic specimens is currently an evolving field for lung cytopathology. The application of these molecular analyses on tyrosine kinase inhibitor-resistant non-small cell lung cancers raises unique technical, biologic, and clinical challenges., Objective: - To provide an overview of the implementation of next-generation sequencing analysis on endobronchial ultrasound-guided transbronchial needle aspiration samples to detect the molecular aberrations underneath the phenomenon of acquired resistance in patients with non-small cell lung cancers progressing while on the EGFR/ALK tyrosine kinase inhibitor treatment., Data Sources: - Peer-reviewed original articles, review articles, and published guidelines and expert opinion reports were reviewed, together with our single-center experience., Conclusions: - Next-generation sequencing analyses and the endobronchial ultrasound-guided transbronchial needle aspiration procedure may represent a valuable strategy to address the unique requirements of molecular testing on tyrosine kinase inhibitor-resistant non-small cell lung cancers.

Brain metastases from NSCLC are associated with a poor prognosis, and local radiotherapy is the most effective therapeutic strategy. The oncofetal protein IMP3 has been studied extensively, and evidence suggests that its expression is related to shorter overall survival and a more aggressive phenotype in solid malignancies. Here, the prognostic role of IMP3 was investigated in a cohort of patients with NSCLC brain metastases in correlation with survival and tumor histotype. A series of 42 NSCLC brain metastases samples was analyzed by tissue microarray and immunohistochemical staining for IMP3. IMP3 expression was associated with shorter overall survival in the whole series and in subgroups of metastases from non-neuroendocrine pulmonary malignancies and adenocarcinoma metastases. These results indicated that IMP3 is a strong prognostic factor in non-neuroendocrine brain metastases and in particular in patients with adenocarcinoma metastases.

Introduction: Among the several agents targeting the programmed cell death 1 (PD-1) pathway, pembrolizumab is currently the only one approved for the treatment of patients with NSCLC in association with a companion diagnostic assay, the anti-PD-L1 immunohistochemical (IHC) 22C3 PharmDx (Agilent Technologies, Santa Clara, CA) using the Dako Autostainer (Dako, Carpinteria, CA). However, the Dako platform is not present in each pathology department, and this technical limitation is a major problem for the diffusion of the PD-L1 IHC predictive test for pembrolizumab., Methods: The Italian Society of Anatomic Pathology and Cytopathology and the Italian Association of Medical Oncology in an independent, multicenter study compared the in vitro diagnostics PD-L1 IHC 22C3 pharmDx test (Agilent) on the Dako Autostainer and the in vitro diagnostics Ventana PD-L1 (SP263) test on the Ventana BenchMark platform (Ventana Medical Systems, Tucson, AZ). Using serial sections from tissue microarrays, 100 lung adenocarcinomas were locally stained and scored in four centers with the same antibody batches., Results: A high analytical correlation (more than 90% at the lower 95% confidence interval [CI] value) between PD-L1 expression levels obtained with the 22C3 and SP263 assays was observed. At the proposed clinically relevant cutoffs (≥50% and ≥1%), the overall concordances between 22C3 and SP263 data were 0.99 (95% CI: 0.96-1) and 0.80 (95% CI: 0.68-0.91), respectively. The lower agreement between data obtained with the 22C3 and SP263 clones at the cutoff of 1% or higher was mainly related to the lower (about 80%) interrater agreement at this cutoff with each clone., Conclusions: These results indicate a high correlation between PD-L1 IHC expression data obtained with the Agilent PD-L1 IHC 22C3 pharmDx and the Ventana PD-L1 (SP263) tests in NSCLC and suggest that the two assays could be utilized interchangeably as an aid to select patients for first-line and second-line treatment with pembrolizumab and potentially with other anti-PD-1/PD-L1 checkpoint inhibitors., (Copyright © 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Aims: Pulmonary adenofibromas are rare benign fibroepithelial tumours of the lung with unknown histogenesis and an indolent clinical behaviour. Their stroma resembles that of solitary fibrous tumours, whereas the glands are composed of respiratory epithelium organized in a phyllodes-like architecture. Differentiation of pulmonary adenofibromas from other more aggressive intrathoracic tumours is clinically relevant. However, their biology is unknown. Here, we sought to characterize pulmonary adenofibromas at a clinicopathological level and to define whether they could be underpinned by a highly recurrent somatic genetic alteration akin to tumours with similar morphology., Methods and Results: Seven pulmonary adenofibromas were subjected to immunohistochemical analysis for thyroid transcription factor 1 (TTF1), napsin A, cytokeratin 7, E-cadherin, CD99, CD34, CD31, STAT6, oestrogen receptor (ER), progesterone receptor, androgen receptor, bcl-2, and vimentin, as well as electron microscopy and capillary sequencing on microdissected samples to evaluate the presence of NAB2-STAT6 fusion genes and MED12 exon 2 mutations in their discrete components. A control group comprising pulmonary solitary fibrous tumours, pulmonary hamartomas and breast fibroadenomas was also analysed. We confirmed that the stromal elements of pulmonary adenofibromas pertain to the fibroblastic lineage, and show ER overexpression in 71% of cases, whereas the epithelium consists of TTF1-positive, E-cadherin positive bronchiolar elements. A highly recurrent NAB2-STAT6 fusion variant (exon 4-exon 2) was detected in the stroma but not in the epithelium. No MED12 mutations were identified., Conclusions: Here, we demonstrate that pulmonary adenofibromas are neoplastic lesions harbouring the molecular hallmark of solitary fibrous tumours., (© 2017 John Wiley & Sons Ltd.)

The identification of EGFR mutations and their respectively tyrosine kinase inhibitors (TKIs), changed dramatically treatment and survival of patients with EGFR-positive lung cancer. Nowadays, different EGFR TKIs as afatinib, erlotinib and gefitinib are approved worldwide for the treatment of NSCLC harbouring EGFR mutations, in particular exon 19 deletions or exon 21 (Leu858Arg) substitution EGFR mutations. In first-line setting, when comparing with platinum-based chemotherapy, these target drugs improves progression-free survival, response rate and quality of life. Unfortunately, the development of different mechanism of resistance, limits the long term efficacy of these agents. The most clear mechanism of resistance is the development of EGFR Thr790Met mutation. Against this new target, different third-generation EGFR-mutant-selective TKIs, such as osimertinib, rociletinib and olmutinib, showed a great activity. In this review, we summarize the scientific evidences about biology, evaluation and treatment on NSCLC with EGFR T790M mutation., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Lung cancer encompasses a constellation of malignancies with no validated prognostic markers. p16Ink4A expression has been reported in different subtypes of lung cancers; however, its prognostic value is controversial. Here, we sought to investigate the clinical significance of p16Ink4A immunoexpression according to specific staining patterns and its operational implications. A total of 502 tumors, including 277 adenocarcinomas, 84 squamous cell carcinomas, 22 large cell carcinomas, 47 typical carcinoids, 12 atypical carcinoids, 28 large cell neuroendocrine carcinomas, and 32 small cell carcinomas were reviewed and subjected to immunohistochemical analysis for p16Ink4A and Ki67. The spectrum of p16Ink4A expression was annotated for each case as negative, sporadic, focal, or diffuse. Expression at immunohistochemical level showed intra-tumor homogeneity, regardless tumor histotype. Enrichments in cells expressing p16Ink4A were observed from lower- to higher-grade neuroendocrine malignancies, whereas a decrease was seen in poorly and undifferentiated non-neuroendocrine carcinomas. Tumor proliferation indices were higher in neuroendocrine tumors expressing p16Ink4A while non-neuroendocrine malignancies immunoreactive for p16Ink4A showed a decrease in Ki67-positive cells. Quantitative statistical analyses including each histotype and the p16Ink4A status confirmed the independent prognostic role of p16Ink4A expression, being a high-risk indicator in neuroendocrine tumors and a marker of good prognosis in non-neuroendocrine lung malignancies. In this study, we provide circumstantial evidence to suggest that the routinary assessment of p16Ink4A expression using a three-tiered scoring algorithm, even in a small biopsy, may constitute a reliable, reproducible, and cost-effective substrate for a more accurate risk stratification of each individual patient.

Introduction: We evaluated the expression of the oncofetal protein IMP3 in a series of neuroendocrine tumors of the lung, correlating our results with proliferating index Ki67 and with the expression of the two most studied stem cell markers in lung cancer, Nanog and Oct3/4., Methods: A total of 74 patients with a diagnosis of neuroendocrine tumor including 46 cases of typical carcinoid, nine cases of atypical carcinoids, 13 cases of large cell neuroendocrine carcinomas and six cases of small cell carcinomas were enrolled., Results: IMP3 was expressed in 50% of small cell carcinomas, 84% of large cell neuroendocrine carcinomas, 55% of atypical carcinoids and 10% of typical carcinoids. IMP3-positive cases showed significantly decreased overall and disease-free survival time compared with IMP3-negative cases. Nanog was expressed in 50% of small cell carcinomas, 31% of large cell neuroendocrine carcinomas, 33% of atypical carcinoids and 15% of typical carcinoids, and 68% of IMP3-positive tumors were also enriched for Nanog expression. Conversely, Oct3/4 expression could not be detected in all the analyzed series. When combining Ki67 and IMP3 expression we demonstrated that all the cases with a Ki67 index higher than 4% were also IMP3-positive, and their simultaneous expression was a poor prognostic factor., Conclusions: IMP3 is a marker of poor outcome in lung neuroendocrine tumors; its correlation with Nanog expression suggest an implication of IMP3 in stem cell processes and its association with a Ki67 labeling index higher than 4% stratifies a subset of atypical carcinoids with a higher risk of recurrence and mortality.